Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.

Abstract

The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown. We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma1 and PPAR gamma2 splice variants. Both gamma1 and gamma2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma1 was detected at lower levels in liver and heart, whereas both gamma1 and gamma2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPARgamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPARgamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma2/18S in obese females vs 9.9 in lean, P = 0.003). This increase was observed in both male and females. In contrast, no differences were observed in PPAR gamma1/18S mRNA expression. There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma2/gamma1 and the body mass index of these patients. We also observed sexually dimorphic expression with increased expression of both PPAR gamma1 and PPAR gamma2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance. Nutritional regulation of PPAR gamma1 was not seen. In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture. We conclude that: (a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…A first level of interaction is the expression level of the PPARg receptor itself, known to be upregulated by GC 27 and downregulated by its own agonists, 11,28 and that of 11b-HSD1, which is subject to feed-forward regulation by GC 29 and inhibition by PPARg agonism. 16 The present study confirms the downregulation of PPARg expression by its own agonists, and shows that chronic exposure to high levels of CORT did not affect PPARg expression or its agonist-mediated reduction, at least over the short time period studied here.…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…23 BMI has been reported to increase, or to have no impact on, PPARG expression in subcutaneous adipose tissue. [23][24][25] A common coding gene variant, Pro12A-la located in the 5 0 -region specific for PPARG2, is according to a meta-analysis of 40 data sets comprising approximately 19 000 subjects associated with higher BMI in the overweight and obese subset (BMI427 kg/m 2 ). 26 The disparate effects of the Pro12Ala polymorphism on BMI in obese and lean individuals suggest that this genetic variant interacts with other factors, which is consistent with reports that the impact of Pro12Ala on obesity can be modified by fatty acid intake.…”

Effects of Troglitazone in Young First-Degree Relatives of Patients With Type 2 Diabetes

“…The molecular target of these agents is thought to include the nuclear transcription factor peroxisome proliferatoractivated receptor-␥ (PPAR␥), which regulates numerous genes involved in adipocyte differentiation and lipid and glucose metabolism (5). PPAR␥ is mainly expressed in adipose tissue and, to a lesser extent, in muscle (6). The effects of PPAR␥ agonists on insulin sensitivity in skeletal muscle could therefore be indirect, involving adipose tissue PPAR␥ stimulation and leading to reductions in circulating and intramyocellular lipid levels (7)(8)(9)(10)(11) or alterations in the secretion of factors that modulate skeletal muscle insulin action (12)(13)(14).…”